# Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Source: https://onco.cc/key-papers/paper-zaretsky-n-engl-j-med/  
OnCo record `paper-zaretsky-n-engl-j-med` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Paper cited by one pathway page, indexed on Europe PMC as PubMed record 27433843 and published in New England Journal of Medicine; the citing page links this DOI, which is how the record was matched.

## Summary

Background: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.

Methods: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.

Results: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.

Conclusions: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

Indexed on Europe PMC as PubMed record 27433843 (DOI 10.1056/nejmoa1604958). Matched by DOI alone: one pathway page cites this DOI among its external links (the pages are listed under Related), and this page was written so that the citation resolves inside OnCo. No figure has been checked by an editor.

## Fields

- Kind: Key paper
- Last checked: 2026-09-22
- Tags: europepmc-ingest
- Journal: New England Journal of Medicine
- Year: 2016
- DOI: 10.1056/nejmoa1604958
- Authors: Zaretsky JM, Garcia-Diaz A, Shin DS, et al.
- What it means: One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
- Caveats: Matched to the citing OnCo records by DOI alone; the summary reproduces the Europe PMC abstract and no figure has been verified against the full paper.

## Sources

- N Engl J Med 2016: https://doi.org/10.1056/nejmoa1604958
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27433843/
- Europe PMC: https://europepmc.org/article/MED/27433843

## Connected records

- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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